Brain glucose metabolism: Role of nitric oxide.

Abstract

One possible reason for failure in achieving optimal glycemic control in patients with type 2 diabetes (T2D) is that less attention has been paid to the brain, a fundamental player in glucose homeostasis, that consumes about 25% of total glucose utilization. In addition, animal and human studies indicate that nitric oxide (NO) is a critical player in glucose metabolism. NO synthesis from L-arginine is lower in patients with T2D, and endothelial NO synthase (eNOS)-derived NO bioavailability is lower in T2D. NO in the nervous system plays a role in neurovascular coupling (NVC) and the hypothalamic control of glucose sensing and energy homeostasis, influencing glucose utilization. This review explores NO's role in the brain's glucose metabolism. Literature indicates that glucose metabolism is different between neurons and astrocytes. Unlike neurons, astrocytes have a higher rate of glycolysis and a greater ability for lactate production. Astrocytes produce a greater amount of NO than neurons. NO inhibits mitochondrial respiration in both neurons and astrocytes and decreases intracellular ATP. NO-induced inhibition of mitochondrial respiration in neurons is not accompanied by compensatory glycolysis because phosphofructokinase 2.3 (PFK2.3), the most potent activator of PFK1 and thus glycolysis, is subjected to ubiquitylation and proteasomal degradation by cadherin-1 (Cdh1)-activated anaphase-promoting complex/cyclosome (APC/C), which leads to a low glycolytic rate in neurons. In astrocytes, NO inhibits mitochondrial respiration, but astrocytes display compensatory glycolysis by activating the adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway.